Non-obese diabetic (NOD) mice will be injected as newborns with CBA x NOD F1 spleen cells and the induction of neonatal tolerance (measured as graft rejection and mixed lymphocyte culture responsiveness) will be correlated with the prevention of insulitis and diabetes. If the mice do not become tolerant following spleen cell injection alone, they will be T cell depleted in vivo and injected with T-depleted F1 spleen and marrow cells, and their protection from insulitis and diabetes will again be correlated with the induction of tolerance and chimerism. T cell depletion will be with a single injection of rat monoclonal CD 4 and CD 8 antibodies. Animals to be treated will include newborn (control and F1 spleen cell injected) as well as 2 and 5 week old NOD who will not receive F1 spleen cells. Preliminary data indicates that either newborn injection with F1 spleen cells, or injection with CD 4 plus CD 8 antibodies at 5 weeks of age, reduce the incidence of insulitis. The mechanism of this protection will be investigated by transfer of spleen cells from experimental animals into irradiated 8 week old NOD recipients, who will be followed for the development of glycosuria. Spleen cells from mature NOD donors will be transferred into irradiated experimental recipients. The role of the donor cells will be tested by reversal of chimerism with anti-MHC antibody, and the role of their MHC restriction by thymectomy and grafting with parental of F1 thymus. The results will indicate strategies by which susceptibility to auto-immune disease can be reduced before irreversibly target organ damage, and as such will be useful in the planning of treatment for man.